Vitamin D and the Regulation of Iron Metabolism: Implications for Anemia of Inflammation Open Access

Smith, Ellen Margaret (2016)

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Vitamin D deficiency and anemia are highly prevalent in the general population, and several chronic diseases including cardiovascular disease and chronic kidney disease carry increased risk for both conditions. Vitamin D deficiency has been identified as a risk factor for anemia in epidemiologic studies, and in vitro studies suggest that vitamin D may reduce cytokine release and hepcidin expression, markers involved in the etiology of anemia of inflammation. The purpose of this dissertation was to 1) examine the association between vitamin D status and anemia in generally healthy adults; 2) evaluate the effect of vitamin D supplementation on markers involved in the etiology of anemia; and 3) test the effect of vitamin D supplementation on hemoglobin concentrations in a population at risk for vitamin D deficiency and anemia. These aims were addressed via cross-sectional analyses exploring the association between 25-hydroxyvitamin D [25(OH)D] concentrations and anemia/hemoglobin, in a racially diverse cohort of employees of Emory University, and among Vietnamese women of reproductive age. We then used a double-blind placebo-controlled trial of healthy adults randomized to receive a one-time oral dose of 250,000 IU of vitamin D3 or placebo to test the effects of vitamin D supplementation on plasma pro-inflammatory cytokine, hepcidin, and ferritin concentrations measured at baseline and one week later. Finally, we tested the effect of vitamin D supplementation on hemoglobin and hepcidin concentrations using a double-blind, placebo-controlled trial of critically ill adults randomized to receive 500,000 IU D3, 250,000 IU D3, or placebo. In generally healthy adults, serum 25(OH)D concentrations <20 ng/mL were associated with lower hemoglobin concentrations and increased odds of anemia, particularly anemia of inflammation. High-dose vitamin D3 supplementation reduced circulating hepcidin concentrations after one week among healthy adults; there were no changes in cytokine or ferritin concentrations. In critically ill adults, treatment with high-dose vitamin D3 resulted in increased hemoglobin concentrations over time; hepcidin concentrations did not change over time. These results provide preliminary evidence of a role for vitamin D in the regulation of iron metabolism. Larger clinical trials are warranted to fully evaluate the therapeutic efficacy of vitamin D in improving anemia.

Table of Contents

CHAPTER 1: Introduction 1

Vitamin D 1

Sources and metabolism of vitamin D 1

Functions of vitamin D 4

Vitamin D requirements 6

Vitamin D deficiency and toxicity 7

Iron and Anemia 9

Sources and metabolism of iron 10

Functions of iron 13

Iron requirements 14

Iron deficiency and toxicity 14

Anemia 17

Purpose of Research 20

CHAPTER 2: Vitamin D and anemia: insights into an emerging association 24

Abstract 25

Introduction 26

Mechanism of action in the vitamin D - anemia association 26

Inflammation and hepcidin 27

Erythropoiesis 29

Other calciotropic hormones and anemia 30

Fibroblast Growth Factor-23 (FGF-23) 30

Parathyroid Hormone (PTH) 31

Epidemiology of the vitamin D deficiency and anemia association 31

Association of vitamin D with subtypes of anemia and racial differences in the association 32

Clinical trials 33

Implications for clinical practice 34

Conclusions 35

Key points 36

CHAPTER 3: Vitamin D deficiency is associated with anaemia among African Americans in a U.S. cohort 42

Abstract 44

Introduction 45

Materials and Methods 46

Study population 46

Data collection 47

Definitions 48

Statistical analysis 49

Results 51

Participant characteristics 51

Associations of vitamin D status with markers of iron status 53

Association of vitamin D status with anaemia 53

Association of vitamin D status with subtypes of anaemia 54

Discussion 55

CHAPTER 4: Dietary vitamin D intake, vitamin D status, and associations with anemia in women of reproductive age in rural northern Vietnam 73

Abstract 75

Introduction 76

Methods and materials 78

Study population 78

Data collection and processing 79

Dietary intake 79

Biochemical and anthropometric measurements 79

Demographic data 80

Definitions 81

Statistical analyses 82

Results 83

Participant characteristics 83

Distribution and determinants of dietary vitamin D intake 83

Associations of vitamin D intake with hemoglobin and anemia 84

Association of dietary vitamin D intake with 25(OH)D status 85

Determinants of 25(OH)D concentration and association of 25(OH)D with hemoglobin and anemia 86

Discussion 87

CHAPTER 5: High-dose vitamin D3 reduces circulating hepcidin concentrations: a pilot, randomized, double-blind, placebo-controlled trial in healthy adults 99

Abstract 101

Introduction 103

Materials and Methods 104

Subjects and protocol 104

Analytic procedures 105

Statistical analysis 106

Results 107

Participant characteristics 107

Effect of high-dose vitamin D on pro-inflammatory cytokine concentrations 108

Effect of high-dose vitamin D on plasma hepcidin concentrations 108

Effect of high-dose vitamin D on plasma ferritin concentrations 109

Discussion 109

CHAPTER 6: High-dose vitamin D3 administration is associated with increases in hemoglobin concentrations in mechanically ventilated critically ill adults: a pilot, double-blind, randomized placebo-controlled trial 122

Abstract 123

Introduction 125

Methods 126

Study design and participants 126

Data collection 128

Statistical analysis 129

Results 130

Sensitivity analyses 132

Discussion 132

CHAPTER 7: Discussion and conclusion 141

Key points 141

Strengths and limitations 145

Implications of this research 147

Future directions 151

Populations to study 152

Form and dose of vitamin D, duration of study 154

Iron and vitamin D biomarkers 156

Other mechanisms of action of vitamin D 156

Interplay of vitamin D with other regulators of iron metabolism 159

Lifestyle factors and functional outcomes 160

Conclusion 161


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